Deregulated Myc expression drives many human
cancers, including
Burkitt's lymphoma and a highly aggressive subset of
diffuse large cell lymphomas. Myc-driven
tumors often display resistance to chemotherapeutics because of acquisition of mutations that impair the apoptosis pathway regulated by the Bcl-2
protein family. Given the need to identify new
therapies for such
lymphomas, we have evaluated the efficacy of
ABT-737, a small molecule that mimics the action of the BH3-only
proteins, natural antagonists of the prosurvival Bcl-2
proteins.
ABT-737 selectively targets certain prosurvival
proteins (Bcl-2, Bcl-x(L), and Bcl-w) but not others (Mcl-1 and A1). We treated mice transplanted with
lymphomas derived either from Emu-myc transgenic mice or Emu-myc mice that also expressed an Emu-bcl-2 transgene. As a single agent,
ABT-737 significantly prolonged the survival of mice transplanted with the myc/bcl-2
lymphomas but was ineffective for the myc
lymphomas, probably because of the relatively higher Mcl-1 levels found in the latter. Strikingly, when combined with low-dose
cyclophosphamide,
ABT-737 produced sustained disease-free survival of all animals transplanted with two of three myc/bcl-2
lymphomas tested. The combination
therapy was also more effective against some myc
lymphomas than treatment with either agent alone. Our data suggest that antagonism of Bcl-2 with small organic compounds is an attractive approach to enhance the efficacy of conventional
therapy for the treatment of Myc-driven
lymphomas that over-express this prosurvival molecule.